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Int. J. Mol. Sci. 2017, 18(11), 2356; https://doi.org/10.3390/ijms18112356

Effect of Intranasally Delivered rh-VEGF165 on Angiogenesis Following Cerebral Hypoxia-Ischemia in the Cerebral Cortex of Newborn Piglets

1
Department of Pediatrics, Drexel University College of Medicine, St. Christopher’s Hospital for Children, Philadelphia, PA 19134, USA
2
Department of Pediatrics, Sanford School of Medicine, University of South Dakota, Sanford Children’s Hospital, Sioux Falls, SD 57105, USA
3
Department of Pediatrics, Division of Neonatology, Children’s National Medical Center, School of Medicine and Health Sciences, George Washington University, Washington, DC 20010, USA
4
Department of Pediatrics and Emergency Medicine, Children’s National Medical Center, School of Medicine and Health Sciences, George Washington University, Washington, DC 20010, USA
5
College of Pharmacy and Allied Health Professions, South Dakota State University, Brookings, SD 57007, USA
6
Department of Pediatrics, Driscoll Children’s Hospital, Texas A&M College of Medicine, Corpus Christi, TX 77807, USA
These authors contributed equally to this work.
*
Author to whom correspondence should be addressed.
Received: 12 September 2017 / Revised: 28 October 2017 / Accepted: 3 November 2017 / Published: 7 November 2017
(This article belongs to the Special Issue Neuroprotective Strategies 2017)
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Abstract

Background: Vascular endothelial growth factor (VEGF) stimulates vascular genesis and angiogenesis. Cerebral Hypoxia-Ischemia (HI) leads to the reduction of vasculature in the cerebral cortex of newborn piglets. Objective: The present study tests the hypothesis that post-hypoxia intranasal administration of recombinant human VEGF165 (rh-VEGF165) for 3 days increases the vascular density in the cerebral cortex of newborn piglets without promoting neovascularization. Design/Methods: Ventilated newborn piglets were divided into three groups (n = 5/group): normoxic (Nx), hypoxic-ischemic (HI), and HI treated with intranasal rh-VEGF165rh-VEGF165 (HI-VEGF). HI piglets were exposed to HI (0.05 FiO2) for 30 min. Recombinant h-VEGF165 (100 ng/kg) was administered 15 min after HI and then once daily for 3 days. The animals were perfused transcardially and coronal brains sections were processed for Isolectin, Hoechst, and ki-67 cell proliferation marker staining. To assess the vascular density, 30–35 fields per animal section were manually counted using image J software. Results: The vascular density (vessels/mm2) was 42.0 ± 8.0 in the Nx group, 26.4 ± 4.8 (p < 0.05 vs. Nx) in the HI group, and 46.0 ± 11.9 (p < 0.05 vs. HI) in the HI-VEGF group. When stained for newly formed vessels, via Ki-67 staining, the vascular density was 5.4 ± 3.6 in the Nx group (p < 0.05 vs. HI), 10.2 ± 2.1 in the HI group, and 10.9 ± 2.9 in the HI-VEGF group (p = 0.72 vs. HI). HI resulted in a decrease in vascular density. Intranasal rh-VEGF165rh-VEGF165 resulted in the attenuation of the HI-induced decrease in vascular density. However, rh-VEGF165 did not result in the formation of new vascularity, as evident by ki-67 staining. Conclusions: Intranasal rh-VEGF165 may prevent the HI-induced decrease in the vascular density of the brain and could serve as a promising adjuvant therapy for hypoxic-ischemic encephalopathy (HIE). View Full-Text
Keywords: VEGF; hypoxia-ischemia; angiogenesis; HIE; neonate; neurology; hypoxia VEGF; hypoxia-ischemia; angiogenesis; HIE; neonate; neurology; hypoxia
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This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited (CC BY 4.0).
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Jain, A.; Kratimenos, P.; Koutroulis, I.; Jain, A.; Buddhavarapu, A.; Ara, J. Effect of Intranasally Delivered rh-VEGF165 on Angiogenesis Following Cerebral Hypoxia-Ischemia in the Cerebral Cortex of Newborn Piglets. Int. J. Mol. Sci. 2017, 18, 2356.

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